Herpes viruses inflict a wide range of diseases against humans and animals. For instance, herpes simplex viruses, types 1 and 2 (HSV-1 and HSV-2), are responsible for cold sores and genital lesions, respectively; varicella zoster virus (VZV) causes chicken pox and shingles; and the human cytomegalovirus (HCMV) is a leading cause of opportunistic infections in immunosuppressed individuals.
Over the past two decades, a class of compounds known as the purine and pyrimidine nucleoside analogs has received the most attention by investigators in the search for new therapeutic agents for treatment of infections. Another nucleoside analog, ganciclovir, has been used with some success in treating HCMV infections.
Nevertheless, in spite of some significant advances, the need for effective, safe therapeutic agents for treating herpes viral infections continues to exist. For a review of current therapeutic agents in this area, see R. E. Boeheme et al., Annual Reports in Medicinal Chemistry, 1995, 30, 139.
Azetidin-2-one derivatives have been reported in the literature as having variety of biological activities; mainly antibacterial, antiinflammatory, antidegenerative, etc. However, azetidin-2-one derivatives have not been reported to be antiviral agents against herpes viruses.
The following references disclose azetidin-2-ones having biological activity:
S. K. Shah et al., European patent application 0,199,630, Oct. 29, 1986, PA0 S. K. Shah et al., European patent application 0,377,549, Oct. 18, 1989, PA0 P. L. Durette and M. Maccoss, U.S. Pat. No. 5,100,880, Mar. 31, 1992, PA0 P. L. Durette and M. Maccoss, U.S. Pat. No. 5,104,862, Apr. 14, 1992, PA0 W. K. Hagmann et al., Bioorg. Med. Chem. Lett. 1992, 2, 681, PA0 W. K. Hagmann et al., J. Med. Chem. 1993, 36, 771, PA0 J. B. Doherty et al., U.S. Pat. No. 5,229,381, issued Jul. 20, 1993, PA0 S. K. Shah et al., Bioorg. Med. Chem. Lett. 1993, 3, 2295, PA0 G. Crawley, PCT patent WO 95/02579, published Jan. 26, 1995, PA0 P. E. Finke et al., J. Med. Chem. 1995, 38, 2449, and K. Kobayashi et al., Japanese patent application 07242624, published Sep. 19, 1995; Chem. Abstr. 1996, 124, 29520. PA0 R.sub.2 and R.sub.3 each independently is hydrogen or C.sub.1-3 alkyl; PA0 R.sub.4 is hydrogen, lower alkyl, methoxy, ethoxy, or benzyloxy; PA0 R.sub.5 is lower alkyl, lower cycloalkyl, (CH.sub.2).sub.m C(O)OR.sub.6 PA0 phenyl, phenyl monosubstituted, disubstituted or trisubstituted with a substituent selected independently from the group consisting of lower alkyl, lower alkoxy, lower alkylthio, halo, hydroxy and amino; phenyl(lower alkyl), phenyl(lower alkyl) monosubstituted or disubstituted on the phenyl portion thereof with a substituent selected independently from the group consisting of lower alkyl, lower alkoxy, lower alkylthio, halo, hydroxy, nitro, amino, lower alkylamino, di(lower alkyl)amino, lower acylamino, di(lower alkyl)aminocarbonyl, cyano, trifluoromethyl, (trifluoromethyl)thio, (trifluoromethyl)sulfinyl, (trifluoromethyl)sulfonyl PA0 Het or Het(lower alkyl) wherein Het represents an unsubstituted, monosubstituted or disubstituted five or six membered, monovalent heterocyclic ring containing one or two heteroatoms selected from the group consisting of N, O or S, wherein each substituent is selected independently from the group consisting of lower alkyl, lower alkoxy, halo and hydroxy; PA0 5-(benzo[1,3]dioxolyl)methyl, (1(R)-1-naphthalenyl)ethyl, 2-benzothiazolyl or 2-thiazolo[4,5-b]pyridinyl; or PA0 R.sub.4 and R.sub.5 together with the nitrogen atom to which they are attached form a piperidino, morpholino, thiomorpholino, piperazino, N-methylpiperazino, 1-(3,4-dihydro-1H-isoquinolinyl) or 2-(3,4-dihydro-1H-isoquinolinyl) or a pyrrolidino ring optionally substituted with benzyloxycarbonyl or with phenyl, said phenyl ring optionally mono- or di-substituted with a substituent selected independently from the group consisting of lower alkyl, lower alkoxy, lower alkylthio, halo, hydroxy, nitro, amino, lower alkylamino, di(lower alkyl)amino, lower acylamino, di(lower alkyl)aminocarbonyl, cyano, trifluoromethyl, (trifluoromethyl)thio, (trifluoromethyl)sulfinyl, (trifluoromethyl)sulfonyl and C(O)OR.sub.7 wherein R.sub.7 is as defined above; PA0 X is selected from the group consisting of O, S, SO, SO.sub.2, NR.sub.8, wherein R.sub.8 is H or lower alkyl; and PA0 Y is C.sub.1-10 non-cyclic or cyclic alkyl; phenyl(lower alkyl), said phenyl ring optionally mono- or di-substituted with a lower alkyl or lower alkoxy, said phenyl ring being optionally fused with an aromatic ring to form a bicyclic ring, said aromatic ring optionally containing a heteroatom selected from the group consisting of N, O and S; Het or Het(lower alkyl) containing one or more heteroatom selected from the group consisting of N, O, and S, said Het optionally mono- or di-substituted with a lower alkyl or lower alkoxy group; said heterocyclic ring being optionally fused with an aromatic ring to form a bicyclic ring, said aromatic ring optionally containing one or more heteroatom selected from the group consisting of N, O and S; C(O)R.sub.9 wherein R.sub.9 is lower alkyl or phenyl(lower alkyl); PA0 or when X is NR.sub.8, wherein R.sub.8 is lower alkyl and Y is lower alkyl or lower alkoxy, X and Y are joined together to form a morpholino or piperidino ring; PA0 or a therapeutically acceptable acid addition salt thereof. PA0 R.sub.2 and R.sub.3 each independently is hydrogen, methyl or ethyl; PA0 R.sub.4 is hydrogen or lower alkyl; PA0 R.sub.5 is phenyl optionally substituted with a substituent selected independently from the group consisting of lower alkyl, lower alkoxy; phenyl(lower alkyl) optionally mono- or di-substituted on the phenyl portion thereof with a substituent selected independently from the group consisting of lower alkyl, lower alkoxy, nitro, halo, cyano, trifluoromethyl, and C(O)OR.sub.7 wherein R.sub.7 is lower alkyl or phenyl(lower alkyl); PA0 Het(lower alkyl) wherein Het represents a five or six-membered, monovalent heterocyclic ring containing a heteroatom selected from the group consisting of N, O, or S, said ring being optionally substituted with lower alkyl or lower alkoxy; PA0 or R.sub.4 and R.sub.5 together with the nitrogen atom to which they are attached form a pyrrolidino optionally substituted with benzyloxycarbonyl or phenyl said phenyl ring optionally mono- or di-substituted with halo, nitro, cyano or trifluoromethyl; PA0 X is selected from the group consisting of O, S, NR.sub.8, wherein R.sub.8 is H or lower alkyl; and PA0 Y is C.sub.1-10 non-cyclic or cyclic alkyl; phenylcarbonyl; phenyl or benzyl optionally mono- or di-substituted with lower alkyl or lower alkoxy, said phenyl ring being optionally fused with an aromatic ring to form a bicyclic ring, said aromatic ring optionally containing a heteroatom selected from the group consisting of N, O and S; and PA0 Het or CH.sub.2 -Het containing one or more heteroatom selected from the group consisting of N, O, and S, said Het optionally mono- or di-substituted with a lower alkyl or lower alkoxy group; said heterocyclic ring being optionally fused with an aromatic ring to form a bicyclic ring, said aromatic ring optionally containing one or more heteroatom selected from the group consisting of N, O and S; PA0 or when X is NR.sub.8, wherein R.sub.8 is lower alkyl and Y is lower alkyl, X and Y are joined together to form a piperidino ring. PA0 R.sub.4 is hydrogen or C.sub.1-3 alkyl; PA0 R.sub.5 is phenyl optionally substituted with a substituent selected independently from the group consisting of lower alkyl or lower alkoxy; (C.sub.1-2 alkyl)phenyl optionally mono- or di-substituted on the phenyl portion thereof with a substituent selected independently from the group consisting of lower alkyl, lower alkoxy, nitro, halo, cyano, trifluoromethyl, and C(O)OR.sub.7 wherein R.sub.7 is lower alkyl or (lower alkyl)phenyl; PA0 X is selected from the group consisting of O, S, NR.sub.8, wherein R.sub.8 is H or lower alkyl; and PA0 Y is lower non-cyclic or cyclic alkyl; phenyl optionally mono- or di-substituted with lower alkyl or lower alkoxy; or PA0 Het containing one or more heteroatom selected from the group consisting of N, O, and S, said Het optionally mono- or di-substituted with a lower alkyl; said heterocyclic ring being optionally fused with an aromatic ring to form a bicyclic ring, said aromatic ring optionally incorporating one or more heteroatom selected from the group consisting of N, O and S; PA0 or when X is NR.sub.8, wherein R.sub.8 is lower alkyl and Y is lower alkyl, X and Y are joined together to form a piperidino ring. PA0 R.sub.4 is hydrogen or methyl; PA0 R.sub.5 is benzyl optionally mono-substituted on the phenyl portion thereof with nitro or trifluromethyl, or 1(R)-phenylethyl; PA0 X is S; and PA0 Y is pyrimidine optionally substituted with lower alkyl; pyridine; N-Me-tetrazole; or benzoxazole. PA0 Step a: Intermediate V is prepared according to known procedures starting from suitably protected D-aspartic acid (ref. P. E. Finke et al., J. Med. Chem. 1995, 38, 2449). PA0 Step b: The acid function of intermediate V is reduced to give alcohol IV. PA0 Step c: When X is O or S, and Y is aryl or Het, the primary alcohol IV is converted into intermediate II, using Mitsunobu reaction conditions (Ref. D. L. Hughes, Org. Reaction 1992, 42, 335; J. R. Dormoy, Synthesis 1982, 753). PA0 Step d: Key intermediates II or II' are converted to the desired inhibitor via deprotection using fluoride ions (e.g. cesium fluoride), followed by condensation with the appropriate reagent. PA0 a) Reduction of acid 2 was achieved with borane in tetrahydrofuran or via the formation of a mixed anhydride with isobutylchloroformate in the presence of an organic tertiary amine e.g. N-methylmorpholine or diisopropylethylamine, and subsequent treatment of the mixed anhydride with sodium borohydride. PA0 b) Conversion of the alcohol 3 into arylether or arylthioether 4 was achieved using Mitsunobu reaction conditions (Ref. D. L. Hughes, Org. Reaction 1992, 42, 335; J. R. Dormoy, Synthesis 1982, 753) for example using triphenylphosphine and diethyl azodicarboxylate in a solvent such as tetrahydrofuran and in the presence of an arylthiol or arylalcohol. PA0 c, d) Intermediate 4 was converted to the desired inhibitor 1 via deprotection using a source of fluoride ions such as cesium fluoride, followed by condensation with the appropriate isocyanate R.sub.5 --NCO in the presence of a tertiary amine such as diisopropylethylamine or preferably lithium (or potassium) bis(trimethylsilyl)amide [when R.sub.4 is H]. Alternatively, an activated carbamate such as phenoxycarbamate could be used. When R.sub.4 is not hydrogen, an appropriate carbamoyl chloride derivative should be used. PA0 a) The alcohol 3 was converted into a leaving group such as an iodide 5. PA0 b) The iodide 5 was then reacted with a secondary amine such as piperidine or morpholine to give 6 wherein X and Y are joined to form a piperidino or morpholino ring respectively. PA0 c) The intermediate 6 was then elaborated as described above to yield a compound of formula 1. PA0 d) PA0 a, b) The primary alcohol 3 was oxidized to the corresponding aldehyde using oxalyl chloride-activated dimethyl sulfoxide (K. Omura and D. Swern, Tetrahedron 1978, 34, 1651) or triacetoxy periodinane (D. B. Dess and J. C. Martin, J. Org. Chem. 1983, 48, 4155). This aldehyde was then reacted with an appropriate Grignard reagent such as methylmagnesium bromide to give the addition product 7 as a mixture of diastereoisomers. PA0 c, d) Conversion of the secondary alcohols 7 into arylether or arylthioether 8 was achieved using Mitsunobu reaction conditions as exemplified in Scheme B, step b. The two diastereoisomers could then be separated using chromatography on silica gel or by preparative HPLC. PA0 e, f) The desired inhibitor 1 was obtained via deprotection and condensation as described above. PA0 a) Benzylic bromide 11 was reacted with methylamine in ethanol to afford the corresponding secondary amine 12 which was isolated as the hydrochloride salt. PA0 b) Further reaction with phosgene in presence of a tertiary organic base such as diisopropylethylamine in dichloromethane gave the desired carbamoyl chloride 13. ##STR10## PA0 a, b) Amine 16 was protected by reaction with di-tert-butylcarbonate in the presence of an aqueous base such as sodium hydroxide. The protected amine was reacted a benzyl halide such as benzyl bromide or chloride in presence of a base such as sodium hydride in tetrahydrofuran to give intermediate 17. PA0 c) Cyclisation of intermediate 17 was accomplished using strong base such as n-butyllithium in the presence of tetramethylethylenediamine in tetrahydrofuran to give pyrrolidine derivative 18. PA0 d, e) Cleavage of the tert-butyloxycarbonyl group is carried out under anhydrous acidic conditions followed by reaction with phosgene in presence of a tertiary organic base such as diisopropylethylamine in dichloromethane to give the desired carbamoyl chloride 19. ##STR12## PA0 a, b) The hydroxy group of the primary alcohol 3 was converted into a leaving group such as 4-nitrobenzenesulfonate, followed by displacement with potassium thioacetate to generate the corresponding thioacetate 21. PA0 c, d) Saponification of the acetate 21 in the presence of lithium hydroxide in methanol followed by addition of methyl iodide gave the desired methylthioether derivative. Deprotection and ureido formation as described above led to the desired compound 1. ##STR14##